4-oxa-5-hydroxymethyl-steroids



United States Patent 3,484,456 4-0XA-5-HYDROXYMETHYL-STEROIDS OskarJeger, Zollikerberg, Zurich, Hans Ueli Wehrli,

Schalfhausen, and Kurt Schatfner, Zurich, Switzerland, assignors to CibaCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledNov. 23, 1966, Ser. No. 596,424 Claims priority, applicationSwitzerland, Nov. 30, 1965 16,492/ 65 Int. Cl. C07d 101/00; A61k 27/00;B01j ]/10 US. Cl. 260-3432 4 Claims ABSTRACT OF THE DISCLOSURE3-oxo-4-oxa-5-hydroxymethy1 steroids and their esters and ethers, aswell as a process for preparing these compounds, which comprisesirradiating with ultra-violet light a 3-0xo-4-RO-S-hydroxysteroid, inwhich R represents a member selected from the group consisting ofhydrogen and lower alkanecarbonyl to obtain the corresponding3-oxo-4-oxa-5-hydroxymethyl steroid. The products are useful, interalia, as antiandrogenic and antiestrogenic compounds and compounds whichinhibit the hypophysis.

The present invention relates to the manufacture of a new group ofsteroids, namely the 3-oxo-4-oXa-5-hydroxymethylsteroids, of theiresters and ethers.

It is known that when 3-oxo-4,5-oxidoor 3-oxo-4-sulphonyloxy-S-hydroxysteroids are irradiated with ultraviolet light,3,6-dioxo-A-nor-B-hornosteroids are obtained according to the followingpartial formulae:

ci/ (In) p-TOS' SH where R stands, for example, for hydrogen or acetyl.

The starting materials to be used in the new process belong preferablyto the androstane, pregnane, cholane, cholestane, spirostane orcardanolide series; their ring system and side-chain may contain one orseveral substituents such, for example, as free or functionally modifiedhydroxyl or keto groups, for example acyloxy groups 3,484,456 PatentedDec. 16, 1969 of carboxylic acids containing up to 20 carbon atoms, suchas acetoxy, propionoxy, benzoyloxy groups, lower alkoxy such as methoxyor ethoxy groups, the tetrahydropyranyloxy group or lower alkylenedioxy,such as ethylenedioxy, 1,2- or 1,3-propylenedioxy groups; furthermorelower aliphatic hydrocarbon residues, for example lower alkyl, alkylene,alkenyl or alkinyl groups such as methyl, ethyl, propyl, methylene,vinyl, allyl, ethinyl or propargyl groups, or halogen such as fluorineor chlorine atoms. The starting materials may also contain one orseveral double bonds.

The acyloxy group in the 4-position of the starting materials contain asacyl radical more especially the residue of a lower alkanecarboxylicacid, for example of acetic or propionic acid.

Preferred starting materials are those of the formula CH CH where Rrepresents a hydrogen atom or a lower alkanoyl residue, especially theacetyl radical, R stands for a hydrogen atom or an a-positioned loweralkyl group and R for an 0x0 or lower alkylenedioxy group or a free,esterified or etherified fl-positioned hydroxyl group together with ahydrogen atom or a lower aliphatic hydrocarbon residue.

The irradiation according to this invention is advantageously carriedout in an organic solvent, for example in an aliphatic, cycloaliphaticor aromatic hydrocarbon such as pentane, hexane, cyclohexane,methylcyclohexane, benzene or toluene, in an alcohol such as ethanol ortertiary butanol and/or an ether such as diethyl ether or dioxan, atroom temperature or with cooling or heating, in the presence or absenceof a basic agent and/or in an inert gas.

The irradiation is carried out with artificial or strong natural light.A preferred source of light is a mercury vapour low or high pressureburner.

Any esters or protective groups, such as ketals, present in theresulting 4-oxa compounds may be split hydrolytically, and free hydroxylgroups may be oxidized to oxo groups. On the other hand, processproducts that contain free hydroxyl groups may be converted in knownmanner into their esters or ethers, for example by acylation withcarboxylic acid anhydrides or carboxylic acid halides or by reactionwith dihydropyran.

Starting materials that contain a possibly esterified 4-hydroxyl groupcan be obtained, for example, by hydroxylating a A -3-oxosteroid in the4,5-position with hydrogen peroxide in the presence of osmium tetroxideand, if desired, reacting the resulting dihydroxy compound with areactive functional derivative of a lower aliphatic carboxylic acid inthepresence of a base, for example pyridine. Alternatively, a A-3-oxosteroid may be reacted in a reaction vessel equipped with a waterseparator with a lower alcohol, especially a lower glycol such as ethyleneglycol, in a boiling hydrocarbon such as benzene or toluene, in thepresence of an organic carboxylic acid, advantageously analkenedicarboxylic acid such as oxalic, succinic or preferably adipicacid, to form the A -3-ketal, hydroxylating the latter in the4,5-position for instance with osmium tetroxide in an organic base, suchas pyridine, treating the resulting osmium compound with hydrogensulphide, converting the resulting 4,5-dihydrxysteroid-3-ketal into the4-acyloxy compound as described above and liberating the 3-oxo group inknown manner.

The process products are pharmocologically active substances or valuableintermediates for use in the manufacture thereof. Thus, for example, theprocess products of the androstane series possess an antiandrogenic andantioestrogenic action and inhibit the hypophysis. When the productobtained belongs to the pregnane, cholane, cholestane, spirostane orcardanolide series it may, if desired, be converted in known manner intothe pharmacologically active compounds, for example by acylolysis,oxidation and/ or by microbiological methods.

The following examples illustrate the invention without restricting itin any manner:

EXAMPLE 1 500 mg. of 3-oxo-4,3,5fi-dihydroxy-17fl-acetoxyandrostane in160 ml. of absolute benzene are irradiated for 6 hours at roomtemperature under nitrogen in a quartz vessel equipped with a mercuryhigh-pressure burner. The batch is evaporated under vacuum and theresidue is chromatographed on silica gel. A 2: l-mixture ofhexane-i-acetone elutes 350 mg. of crystalline 3-oXo-5-hydroxymethyl-17,8-acetoxy-4-oxa-androstane. After three recrystallizations fromacetone+petroleum ether the product melts at 213-216 C. In the infraredspectrum it reveals bands at 36003350, 1725 and 1250 cm.

EXAMPLE 2 A mixture of 2.5 g. of 3-oxo-4,8,5fl-dihydroxy-175-acetoxyandrostane and 20 ml. of a lzl-mixture of aceticanhydride+pyridine is kept overnight at room temperature, and thesolution is then evaporated under vacuum. The resulting3-oxo-4fl,17fl-diacetoxy-5,8-hydroxyandrostane is redissolved fromacetone-l-petroleum ether; it melts at 225 to 226 C. Optical rotation[a] =+50 (c.=0.61). Infrared bands: 3590, 1745, 1726 and 1250 cmr' 500mg. of the compound obtained in this manner are irradiated in 160 mg. ofabsolute benzene for 3 hours as described in Example 1. Chromatographyof the crude product on silica gel in a 2:1-solution of benzene-i-ethylacetate yields 424 mg. of crystals which, after three recrystallizationsfrom acetone-l-petroleum ether, melt at 215 to 216 C. The resulting3-oxo-5-acetoxymethyl-17,8- acetoxy-4-oxa-androstane reveals in itsinfrared spectrum bands at 1735 (shoulder), 1725 and 1250 crnf Opticalrotation [u] =+38 (c.:0.53).

EXAMPLE 3 70 mg. of the compounds obtained in Example 1 are acetylatedovernight at room temperature in 5 ml. of a lzl-mixture of aceticanhydride and pyridine, then evaporated under vacuum and the residuedissolved in benzene and filtered through neutral alumina (activityIII), to yield 65 mg. of 3-oxo-5-acetoxymethyl-17(3-acetoxy-4-oxa-androstane which, after four recrystallizations fromacetone+petroleum ether, melts at 210 to 212 C. Optical rotation [a]=+4O.7 (c.=0.74). According to its mixed melting point, infraredspectrum and thin-layer 4 chromatogram this product is identical withthe product obtained in Example 2.

EXAMPLE 4 200 m1. of 3-oxo-5-acetoxymethyl-17B-acetoxy-4-oxaandrostanein 12 ml. of saturated methanolic potassium carbonate solution arehydrolyzed for 1 /2 hours at room temperature. The usual working up andchromatography of the crude product in acetone+ hexane 2:1-solution onsilica gel yields ml. of 3-oxo-5-hydroxymethyl-175-hydroxy-4-oXa-androstane Which, after two recrystallizations fromacetone-l-petroleum ether, melts at 236 C. Optical rotation [a] :|42.5(c.'=0.73), Infrared spectrum: 3610, 34203400 and 1725 cmf The 3 oxo45,5,8-dihydroxy-17fl-acetoxy-androstane used as starting material inthe above examples may be prepared in the following manner:

3 grams of testosterone acetate in 200 ml. of ether are mixed with 100ml. of osmium tetroxide and 12 mm. of hydrogen peroxide. The mixture isstirred for 6 days at room temperature in the dark, then diluted withethyl acetate, washed with potassium iodide solution and sodiumthiosulphate solution and with water. The crude product obtained onevaporation is filtered in ether through silica gel and then redissolvedfrom acetone+ petroleum ether; it melts at to 173 C. Optical rotation[a] =+27 (c.=0.64). Infrared bands at 3600- 3300, 1725 and 1257 cm.

What is claimed is:

-1. A member selected from the group consisting of a compound of theformula Atwater et al.; Jour. Amer. Chem. Soc., vol. 82 (1960), p. 2012.

JAMES A. PATTEN, Primary Examiner US. Cl. X.R.

